Method of hormone treatment for patients with symptoms consistent with multiple sclerosis

ABSTRACT

A method for patients having symptoms consistent with multiple sclerosis comprising administering a regimen of doses of human growth hormone of less than 0.5 mg/day. In one aspect, the method includes replenishing one or more of melatonin, thymus, thyroid, adrenal and sex hormones to predetermined levels in conjunction with the human growth hormone.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] The invention relates to hormone therapy as a treatment forpatients with symptoms consistent with multiple sclerosis.

[0003] 2. Background

[0004] It is known that the levels of a variety of hormones dropsubstantially with age. These include human growth hormone, sexhormones, pineal, adrenal, thyroid, and thymus hormones. Hormonalreplenishment methods employed as anti-aging treatments have beendeveloped. An example of such method is described in U.S. Pat. No.8,855,920. The utility of this method in connection with certaindegenerative diseases, often associated with hormonal deficiencies dueto aging, is also known in the art.

[0005] In contrast, Multiple Sclerosis (MS) is not a disease associatedwith degenerative conditions associated with old age. Rather, MS strikesmainly young adults and is the most common neurologic cause ofdisability in that age group. Overall, MS affects approximately 300,000Americans.

[0006] MS is thought to be an autoimmune illness, wherein the immunesystem mistakenly recognizes normal brain and spinal tissue as “foreign”and attacks them, resulting in inflammation and damage. Myelin, theinsulative material surrounding axons in nerve cells, are particularlyaffected by MS. In patients, the inflammation disrupts myelin, sometimesdestroying the axons thus impeding the connections between nerve cells.The region of demyelination and inflammation within the brain or spinalcord is called a “plaque” and ranges anywhere from millimeters to morethan a centimeter in diameter.

[0007] Actual MS symptoms appear to reflect the number and severity ofplaques as well as their location at important sites within the nervoussystem. Mild sensory symptoms, e.g., tingling, burning, itching, mayresult. Typically, however, no diagnosis of MS is made until severesymptoms develop, such as weakness, paralysis or numbness of limbs, lossof vision, imbalance, chronic pain or chronic fatigue. The long termconsequences of MS can be very debilitating. In some studies, 50% ofpatients were disabled within ten years and fewer than two thirds wereable to walk after thirty years.

[0008] In common diagnosis, MS is found by excluding all other potentialconditions from consideration. Formerly diagnostic chemical tests ofcerebro-spinal fluid determined the presence of MS. This, however, hasgiven way in recent years to magnetic resonance imaging (MRI) scans ofthe brain as the preferred diagnostic method. Brain MRI scans areabnormal in the vast majority of MS victims. Areas of abnormalbrightness, suggesting increased water content, appear on “T2 weighted”scans; dark areas on “T1 weighted” scans suggest focal areas of tissuedestruction; and abnormal brightness after a dye is injected forenhancement into the patient's bloodstream suggest that inflammation hasdamaged the blood-brain barrier. Again, as these symptoms are presentalso in other neurologic conditions, the diagnosis of MS is not madefrom these symptoms alone. This diagnosis results by testing done overtime.

[0009] Various drugs, including natural immune substances such asbeta-interferon, have proved effective in treating the physical symptomsof MS and reducing their frequency. Recently studies with animalsemploying induced experimental autoimmune encephalomyelitis (EAE), ananimal model of MS, has shown that growth factor hormones, includingInsulin-like Growth Factor hormones (IGF) may promote myelinregeneration, reducing and sometimes eliminating inflammatory lesionsand reducing other clinical deficits in EAE subjects. In one study adultfemale mice having induced EAE were injected subcutaneously with 0.6 mgof IGF over a ten day period. Another group of EAE-induced mice weregiven placebos. Those treated with IGF-I exhibited reduced deficits andreduced numbers and sizes of inflammatory, demyelinating anddemyelinated lesions.

SUMMARY

[0010] The invention relates to a hormone replenishment method employedas a treatment for subjects with symptoms consistent with MultipleSclerosis (MS). The method includes, in one aspect, administering aregimen of human growth hormone (HGH) of less than 0.5 mg per day.

BRIEF DESCRIPTION OF THE DRAWINGS

[0011]FIG. 1 illustrates the growth hormone decline in advancing years.

[0012]FIG. 2 illustrates the free testosterone levels in malesthroughout life.

[0013]FIG. 3 illustrates the levels of estrogen and progesterone infemales before and after menopause.

[0014]FIG. 4 illustrates the melatonin levels produced throughout life.

[0015]FIG. 5 illustrates the DHEA levels for males and females over alife span.

[0016]FIG. 6 illustrates the thyroid hormone levels versus age.

[0017]FIG. 7 illustrates the thymus hormone levels versus age.

[0018]FIG. 8 presents the peak IGF-I levels in males before and afteradministration of IGF-I.

[0019]FIG. 9 presents the peak IGF-I levels in females before and afteradministration of IGF-I.

DETAILED DESCRIPTION

[0020] The invention relates to a method useful in treating symptomsconsistent with MS. In one embodiment, the method includes administeringa regimen of doses of HGH of less than 0.5 mg per day. In anotherembodiment, the method includes determining that the level of humangrowth hormone and at least two supplemental hormones are below optimalor predetermined physiological levels for an adult human, andestablishing a regimen for the replenishment of the level of thedeficient hormones to optimal or predetermined physiological levels. Thesupplemental hormones include the sex hormones, namely testosterone,progesterone, and estrogen, the melatonin hormone, the adrenal hormones,namely DHEA and pregnenolone, the thyroid hormone, and the thymushormone.

[0021] One of the hormones that declines sharply with age is humangrowth hormone (HGH, GH, or somatotropin). FIG. 1 illustrates the growthhormone decline in years for an ordinary human.

[0022] HGH is a protein hormone secreted by the somatotropic cells ofthe anterior lobe of the pituitary gland. HGH secretes in a pulsatilemanner throughout a 24-hour period. The pulsatile diurnal output ofgrowth hormone is modulated by a pair of inner synergistic hypothalamushormones, the growth hormone releasing hormone (GHRH) and growth hormoneinhibiting hormone (GHIH) or somatostatin. GHRH and GHIH are synthesizedin the hypothalamus and transported along with other messenger hormonesto the pituitary gland by means of a short specialized portal veinnetwork. GHRH is essentially a series of short pulses, clocked at aboutonce a minute uniformly throughout a 24-hour day. GHIH, on the otherhand, is a “gatekeeper” that is normally abundant, but occasionally low,allowing pulses of growth hormone to be released from the pituitarygland into the bloodstream. The base line level of growth hormone, asfar as serum concentration is concerned, is ordinarily at or belowdetectable limits from hour to hour.

[0023] The major secretion of HGH occurs at night, one to two hoursafter the onset of deep REM sleep. Peek secretion levels are between10-50 mg/ml.

[0024] It is known that physiological roles are probably due both todirect actions of HGH and indirect actions mediated by the peptidehormones known as somatomedins. Somatomedins are stimulatedpredominantly by the action of HGH and include Insulin-like GrowthFactor-I (also known as IGF-I and somatomedin-C) and IGF-II. The majorsite of somatomedin secretions is the liver, but there is also someproduction at peripheral sites.

[0025] Proper human growth from infancy is contingent upon adequategrowth hormone secretion. Growth hormone appears to affect the growth ofvirtually every organ and tissue in the body. In normal development, HGHand the somatomedins are responsible for many manifestations of normalgrowth. Growth hormone deficiency during the childhood growing period ismanifested by profound short stature. This deficiency has been treatedby human growth hormone supplements for many years. However, thescarcity of the source material for natural HGH (i.e., pituitary glandsof cadavers) has limited investigations into other possible applicationsfor HGH. Recently, bioengineered HGH or recombinant HGH has beendeveloped with identical characteristics as the natural HGH and removedthe previous investigation limitations.

[0026] In 1990, a group of researchers published a report that showedthat the declining activity of the IGF-I access with advancing age maycontribute to the decrease in lean body mass and the increase of mass ofadipose tissue that occur with aging. “Effects Of Human Growth HormoneIn Men Over 60 Years Old”, Rudman, D., M.D., et al., The New EnglandJournal of Medicine, Vol. 323, No. 1, Jul. 5, 1990. Subsequent studieshave shown that growth hormone increases bone mass in osteoporosis,reverses declining cardiac function, reverses declining pulmonaryfunction, reverses the decline in immune function associated with aging,increases lean muscle mass, decreases the percentage of body fat, andincrease the capacity for exercise. See Powrie, J. et al., “GrowthHormone Replacement Therapy For Growth Hormone-Deficient Adults”, DrugsVol. 49, No. 5, pages 656-63, 1995; Rosen, T., et al., “Consequences OfGrowth Hormone Deficiency In Adults And The Benefits And Risks OfRecombinant Human Growth Hormone Treatment”, Horm. Rees., Vol. 43, pages93-99, 1995; and Hoffman, A. R., “Growth Hormone Therapy In The Elderly:Implications For The Aging Brain”, Psychoneuro-endocrinology, Vol. 17,No. 4, pages 327-33, 1992 (concluding that it is possible that chronicphysiological GH and/or IGH-I replacement therapy might reverse orprevent some of the inevitable sequelae of aging).

[0027] Optimal or predetermined physiological levels for the hormonesincluded in replenishment as an embodiment of the method of theinvention are set forth in Table I. These levels are set based upon theaverage peak levels for the hormones which are present in adult humansat natural ages of optimal health, vigor and potency- usually in thesecond and third decades of the average life span.

[0028] Table I shows that the HGH is measured by the level of IGF-I.Serum levels of HGH are difficult to measure. IGF-I is directlydependent upon the secretion of HGH by the pituitary gland, so thereforethere is a direct linkage between increased secretion of HGH andincreased production of IGF-I. Table II presents the effects of the lowdose at high frequency human growth hormone administration (lowdose-high frequency) contemplated by the invention on IGF-I (somatomedinC) blood levels. FIGS. 8 and 9 present the peak IGF-I levels in malesand females, respectively, before and after administration of IGF-I.FIGS. 8 and 9 show mean, minimum and maximum, and 25, 50, and 75percentile for 204 males and 91 females, respectively. Table III showsthe data presented in FIG. 8. Table IV shows the data presented in FIG.9. TABLE I METHOD OF TARGET LEVEL HORMONE ADMINISTRATION (μg/ml blood)HGH injection IGF-I = 350 free testosterone gel female =  3 male =  40progesterone capsule 10-25 estrogen capsule 100-200 melatonin capsule18-69 (at 3:00 am) DHEA capsule female = 400 male = 600 thyroid tabletT3 = 150-180 pregnenolone capsule 100-200 thymus hormone Subligualpowder N/A

[0029] TABLE II Effects of Human Growth Hormone Administration (lowdose-high frequency) on Somatomedin C Blood Levels Somatomedin C. BloodLevels (mg/ml) Before hGH After hGH Increase Mean 233.8 384.5 61.0%STDEV 62.3 50.8 SEM 9.1 7.4 No. Patients 47.0 47.0 MAX 366.0 574.0 MIN132.0 301.0 P < 0001

[0030] TABLE III Males IFG MALES MALES MALES MALES PEAK LEVELS BEFOREAFTER CHANGE DAYS SAMPLE SIZE BEFORE 204 MEAN MEAN MEAN MEAN AFTER 204192.3 266.7  74.4 118.5 MEDIAN MEDIAN MEDIAN MEDIAN 183 272.5  75.5  82STDEV STDEV STDEV STDEV  61.7  75.1  73.2 110.3 MIN MIN MIN MIN  21  63135  6 25%ile 25%ile 25%ile 25%ile 147 217  24  40 50%ile 50%ile 50%ile50%ile 183 273  76  82 75%ile 75%ile 75%ile 75%ile 231 325 125 146 MAXMAX MAX MAX 361 396 258 639

[0031] TABLE IV Females FE- FE- FE- FE- IFG MALES MALES MALES MALES PEAKLEVELS BEFORE AFTER CHANGE DAYS SAMPLE SIZE BEFORE 91 MEAN MEAN MEANMEAN AFTER 91 162.2 236.3    74.0 133.4 MEDIAN MEDIAN MEDIAN MEDIAN 154240    72 101 STDEV STDEV STDEV STDEV  61.5  75.1    73.6 113.8 SEM SEMSEM SEM  6.4  5.9    4.8  13.2 MIN MIN MIN MIN  41  52  −93  26 25%ile25%ile 25%ile 25%ile 111 177    26  49 50%ile 50%ile 50%ile 50%ile 164240    72 101 75%ile 75%ile 75%ile 75%ile 205 294   128 173 MAX MAX MAXMAX 311 378   231 534

[0032] The method of determining the level of the select group ofhormones may be accomplished by a simple blood test. A patients' bloodis evaluated for the hormone levels of the select group of hormones andthose levels are compared to the optimal or predetermined physiologicallevels set forth in Table I. Based on the comparison of a patient'shormone levels with the optimal or predetermined physiological levels, aregimen is established for the patient for the replenishment of thelevel of deficient hormones to optimal physiological levels. It isfurther contemplated, that after the initial evaluation and theestablishment of the regimen, a patient is monitored every 30 days, by asimilar blood test, until the patient attains the optimal orpredetermined physiological level, and the dosages of hormonesupplementation are adjusted accordingly. Once the target levels areestablished, the regimen directs that the patient continue to follow theestablished dosage of supplemental hormones indefinitely to maintain theoptimal or predetermined physiological levels. Periodic blood tests aresubsequently administered to assure that the optimal or predeterminedphysiological levels are maintained.

[0033] The optimal or predetermined physiological level of HGH and thesupplemental hormones are set forth in Table I. These levels recognizethe importance of each hormone to the body and are based on studies thatindicate the period of life when the individual hormones are at theirpeak in the human body—generally in the second and third decade of anaverage human life span.

[0034] The method of the invention also contemplates that the HGH isadministered in keeping with the way the pituitary secretes HGHnaturally. The low dose-high frequency method mimics the pituitarygland. The pituitary secretes HGH 24 hours a day, with the peaks duringthe first two hours of sleep. The method contemplates that the patientstake lower doses more frequently to try to mimic the natural rhythm ofthe body as much as possible. The invention contemplates that thepatients take HGH injections at least twice daily. A preferred regimencalls for subcutaneous injections of doses less than 0.5 mg per day(approximately 1-3 I.U.), administered twice daily. Typical doses forthis regimen range from 4 units per week to 8 units per week.

[0035] Because the invention contemplates that human growth hormone isadministered in lower doses that mimic the natural rhythm of the body,the invention contemplates that the patient experiences none of theadverse side effects reported in earlier studies when higherpharmacological doses were given to patients more intermittently, e.g.,3 days per week.

[0036] Aside from the administration of HGH the invention contemplatestherapeutic application of supplemental hormones. The supplementalhormones include the sex hormones, namely testosterone, progesterone,and estrogen, the melatonin hormone, the adrenal hormones, namely DHEAand pregnenolone, the thyroid hormone, and the thymus hormone. Dosagefor administration of the supplemental hormones varies with theparticular hormone.

[0037] The optimal or predetermined physiological level goal intestosterone replacement therapy in men is to maintain a totaltestosterone level at about 900-1200 μg/ml and a free testosterone levelof about 30-40 μg/ml throughout one's lifetime. FIG. 2 illustrates thefree testosterone level in males throughout life and shows the leveldecreasing with advancing age. In women, the levels of testosterone tomaintain are much less, specifically women should maintain a freetestosterone level of about 3 μg/ml.

[0038] Possible side effects which can occur during testosteronereplacement include some weight gain due to accumulation of lean bodymass, fluid retention, and among patients taking supraphysiologic dosesof androgens: decreased testicular size, azoospermia, and acne.

[0039]FIG. 3 illustrates the levels of estrogen and progesterone infemales before and after menopause. As noted above, candidates forsupplemental estrogen or progesterone should replenish these hormonesconcurrently to avoid the risk of side effects. These hormones may betaken in capsule form. The optimal or predetermined target physiologicallevel of progesterone is 10-25 μg/ml blood, and of estrogen is 100-200μg/ml blood.

[0040]FIG. 4 illustrates the melatonin levels produced throughout life.The optimal or predetermined target physiological level of melatonin is18-69 μg/ml determined by the average level of melatonin produced by ahealthy young adult (i.e., 20-25 years). Further, melatoninsupplementation has been shown to be completely harmless to the body andcause no side effects. As noted above, the amount of the adrenal hormoneDHEA peaks in the bloodstream of an individual at about 25 years of age.In one embodiment, FIG. 5 illustrates the DHEA levels for males andfemales over a typical life span. It is the peak physiological levelthat, in one embodiment, is the goal of the DHEA replenishment therapy.The optimal or predetermined physiological level of DHEA in a female is400 μg/ml blood and in a male is 600 μg/ml blood.

[0041] The serum level of pregnenolone for normal adults ranges between50 to 350 μg/ml of blood. If a person's level is low and falls outsideof this range, replacement is recommended. Depending on the degree towhich a patient may be deficient, the dose is approximately 100-200milligrams (“mg”) each day. The older or less healthy a person is, themore likely he or she will feel a dramatic effect from pregnenolone. Ablood test is required to determine each individual's need forpregnenolone replacement, and to assess the proper dosage for therapy.

[0042] Maintaining sufficient thyroid hormone levels is also beneficial.FIG. 6 illustrates thyroid hormone levels versus age. Supplementationwith thyroid hormone, particularly T-3 to 150-180 μg/ml of blood iscontemplated by the invention.

[0043]FIG. 7 illustrates thymus hormone level versus age. Laboratoryresults indicate that the presence of thymus hormone in circulation canhave an effect on a variety of other organ systems. All four thymicpreparations (i.e., thymosin, thymulin, THF, and thymopoietin) arecommercially available. Such a replacement therapy is totally harmless.The Food and Drug Administration has not regulated thymic hormonesbecause they are not yet considered drugs or pharmaceuticals. Thymushormone is in the same status and classification as DHEA and melatoninhormones which are also available over the counter.

[0044] By maintaining the optimal or predetermined physiological levelsof human growth hormone and the supplemental hormones described above,the treatment is effective for reducing symptoms commonly associatedwith MS. As noted in the Background of the Invention section, diagnosisof MS is by exclusion, i.e., all other alternative diagnoses of ademyelinating condition must be ruled out before a diagnosis of MS maybe established. The following case studies of patients withdemyelinating conditions demonstrated from testing are illustrative ofthe effectiveness of the invention in patients with symptoms consistentwith MS:

[0045] Case 1: (43 year old male).

[0046] An MRI of the brain during the first exam in 1995 revealedmultiple white matter signal abnormalities as well as subtle diffusesignal abnormalities consistent with MS. Soon after this test, thepatient was placed on a hormone replenishment regimen, featuring twicedaily subcutaneous doses of human growth hormone in the amount of 0.5mg. per dose. Testosterone, melatonin, DHEA, thyroid, pregnenolone, andthymus hormone were also given in the manner previously described tooptimal levels.

[0047] A later exam in 1998 noted significant diminishment of lesions,including the actual disappearance from the MRI scan of lesions. Theexamining physician noted that the previously noted large left middlecerebellar peduncle lesion was very subtle on the current film and wasinitially interpreted as normal. There was also a small lesion in theanterior limb of the internal capsule seen on the 1995 study which isnot currently visualized. Finally, the examining physician noted thatthere was a right posterior frontal deep white matter lesion that wasslightly smaller than previously noted in 1995 with the remaininglesions noted from the 1995 examination remaining essentially unchanged.Brain evoked response studies also indicate improvement in speed ofneurotransmission after this treatment. For example, visual evokedresponses may reveal optic nerve involvement by MS. Studies of thepatient's visual evoked responses before and after hormone replenishmenttherapy revealed faster conduction speed after the therapy, indicatingimprovement in the optic nerve. The patient also regained complete motorstrength and sensory disturbances disappeared.

[0048] Case 2: (Female 60 years of age):

[0049] Brain MRI scan taken in 1993 revealed multiple punctate foci ofincreased signal intensity on T2 weighted images in the corona radiataand basal ganglia and thalami, compatible with the presence of multiplelacunar infarcts (areas of necrotic tissue). The test also revealedlesions in the deep cerebral structures involving white matter and alesion in the right side pons was observed to be approximately 1.0 cm insize. The conclusion by the examining physician was “thought extensivewidespread infarcts could account for all the above described findings,the patient's age and sex makes this somewhat less likely and ademyeliting process, such as multiple sclerosis must be considered.Certainly this diagnosis could account for all the abnormal findingsseen.”

[0050] In January of 1995, with no observed changes in her condition,the patient initiated hormone replenishment treatment includingsubcutaneous injection twice daily of 0.5 mg Human Growth Hormone, aswell as supplemental hormones such as progesterone, estrogen, DHEA,melatonin and pregnenolone in doses previously described.

[0051] In October 1995 a further brain MRI showed the pontine lesion todecrease in size to approximately 0.4 cm (surrounded by a crescentricmargin of subtle enhancement). With respect to other white matter foci,none showed abnormal enhancement. The examining physician concluded thatthe degree of enhancement had subsided considerably, as had the size ofthe individual pontine lesion. She also fully regained her motorstrength and recovered from sensory disturbances.

[0052] The above case histories indicate that hormone replenishment andsupplementation is effective at reducing the symptoms associated withMS. HGH administration, given in a low dose, high frequency regimen isbelieved particularly to be effective at reducing the symptoms of MS.

[0053] In the foregoing specification, the invention has been describedwith reference to specific exemplary embodiments thereof. It will,however, be evident that various modifications and changes may be madethereto without departing from the broader spirit and scope of theinvention as set forth in the appended claims. The specification anddrawings are, accordingly, to be regarded in an illustrative rather thana restrictive sense.

What is claimed is:
 1. A method comprising: in a human subject havingsymptoms consistent with multiple sclerosis, administering a regimen ofdoses of human growth hormone of less than 0.5 mg. per day.
 2. Themethod of claim 1 , wherein administering the regimen of human growthhormone comprises subcutaneous injections of doses of human growthhormone.
 3. The method of claim 2 , wherein the regimen for injectionscomprises twice daily.
 4. The method of claim 1 , further comprisingprior to administering a regimen of human growth hormone measuring thelevel of human growth hormone in a human subject's blood to determinethat the level of human growth hormone is below a predeterminedphysiological level for an adult human.
 5. The method of claim 4 ,further comprising measuring a level of supplemental hormones selectedfrom the group consisting of sex hormone, melatonin hormone, adrenalhormone, thyroid hormone and thymus hormone to determine that at leastone of the hormones is below a predetermined level for an adult human;and replenishing the level of the at least one supplemental hormone to apredetermined physiological level.
 6. A method comprising: measuring asample of a human subject's blood, the human subject having symptomsconsistent with multiple sclerosis, to determine that the level of humangrowth hormone is below a predetermined physiological level for an adulthuman; and replenishing the level of human growth hormone to thepredetermined physiological level.
 7. The method of claim 6 , whereinreplenishing the level of human growth hormone comprises subcutaneousinjections of doses of human growth hormone.
 8. The method of claim 7 ,wherein a replenishment regimen comprises injections twice daily.
 9. Themethod of claim 6 , further comprising measuring a level of supplementalhormones in the human subject's blood, the supplemental hormonesselected from the group consisting of sex hormone, melatonin hormone,adrenal hormone, thyroid hormone and thymus hormone to determine that atleast one of the hormones is below a predetermined level for an adulthuman; and replenishing the level of the at least one supplementalhormone to a predetermined physiological level.
 10. A kit for treatingsymptoms associated with multiple sclerosis comprising human growthhormone and at least one of the supplemental hormones selected from thegroup consisting of sex hormone, melatonin hormone, adrenal hormone,thyroid hormone, and thymus hormone, the kit for establishing a regimenfor the replenishment of the human growth hormone and the at least oneof the supplemental hormones to predetermined physiological levels. 11.The kit of claim 10 , wherein the amount of human growth hormone isprovided in intravenous unit form in doses of less than 0.5 mg per day.12. The kit of claim 11 , wherein the amount of human growth hormone isadministered twice daily.
 13. The kit of claim 10 , wherein the sexhormone comprises at least one of testosterone, progesterone, andestrogen.